Oncolytic viruses (OV) which replicate selectively in tumor cells are an emerging modality of cancer treatment. Aside from direct cytopathic effects and lysis of tumor cells, interactions of OV with the immune system can trigger systemic anti-tumor immunity. OV have been modified to express immunomodulatory transgenes to further enhance these effects (Melcher et al., Mol Ther. 2011, 19: 1008-1016). The vaccinia virus JX-594 and herpesvirus talimogene laherpavec (TVEC), both harboring GM-CSF, have shown promising results in clinical phase II and III trials (Heo et al., Nat Med. 2013, 19: 329-336 and Andtbacka et al. J Clin Oncol. 2013, 31, suppl; abstr LBA9008).
RNA viruses, in particular members of the family Paramyxoviridae like, e.g. measles virus, have also shown potential use in oncolysis. Viruses of the family Paramyxoviridae are negative-sense single-stranded RNA viruses and include human pathogens like, e.g. human parainfluenza viruses, mumps virus, human respiratory syncytial virus, and measles virus. From wild type measles virus, several non-pathogenic strains, including a vaccine strain, have been derived, which have been shown to remain oncolytic. The measles virus vaccine strain has been developed as a vector platform to target multiple tumor entities and several clinical trials are ongoing (Russell et al., Nat Biotechnol. 2012, 30: 658-670). Recently, the capacity of oncolytic MV encoding GM-CSF to support the induction of a specific anti-tumor immune response in terms of a tumor vaccination effect was demonstrated (Grossardt et al. Hum Gene Ther. 2013, 24: 644-654.).
In general, immune response via T cell activation involves the integration of numerous signals. In order to improve cellular immunity to tumor cells, a variety of immunomodulatory molecules were developed, e.g. “bispecific T cell-engagers” (“BiTEs”). BiTEs are bispecific antibodies, structurally based on two single-chain variable fragments (scFv) with one binding domain targeting the T cell receptor-associated molecule CD3 on T cells and the other domain targeting cell surface molecules on tumor cells. Such crosslinking of even resting T cells to target cells induces an artificial immunological synapse and triggers T cell-mediated target cell lysis. Hence, the BiTE-directed killing is independent of TCR specificity, costimulation and antigen presentation.
There is, however, still a need in the art for improved cancer therapies, in particular for improved oncolytic viruses.